Suppression of aberrant transient receptor potential cation channel, subfamily V, member 6 expression in hyperproliferative colonic crypts by dietary calcium.
Suppression of aberrant transient receptor potential cation channel, subfamily V, member 6 expression in hyperproliferative colonic crypts by dietary calcium.
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DOI：
10.1152/ajpgi.00193.2010
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发表时间：
2010-09
期刊：
影响因子：
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通讯作者：
S. Peleg;J. Sellin;Yu Wang;M. Freeman;S. Umar
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文献类型：
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作者：
S. Peleg;J. Sellin;Yu Wang;M. Freeman;S. Umar
据信膳食钙可以降低结肠癌风险，但其发生机制尚不清楚。采用柠檬酸杆菌啮齿类诱导的可传播的小鼠结肠增生（TMCH）模型，我们以前表明，高钙饮食（hCa）显着废除在NIH-瑞士小鼠远端结肠增生。在这里，我们探讨了膳食保护hCa的机制，通过分析基因的表达参与调节钙吸收/流量在肠上皮细胞，包括钙敏感受体，维生素D受体，钙结合蛋白，和瞬时受体电位阳离子通道，亚家族V，成员5和6（TRPV 5/6）。有趣的是，虽然TRPV 6表达在TMCH期间显著增加，但其他基因产物的表达没有变化。这种升高的TRPV 6表达被hCa饮食显著消除。免疫荧光显示TRPV 6在正常结肠的顶膜定位，而在TMCH期间，我们观察到强烈的顶极和细胞质染色沿着整个纵向隐窝轴，包括扩大的增殖区。hCa饮食逆转了这种效应。在人类中，TRPV 6的过表达与早期结肠癌有关，在结肠癌细胞中，通过小干扰RNA抑制TRPV 6表达可抑制其增殖并诱导凋亡。TRPV 6小干扰RNA也降低了活化T细胞中钙依赖性核因子的转录活性。因此，TRPV 6的异常过表达有助于小鼠中的结肠隐窝增生和人类中的结肠癌细胞增殖。因此，可能需要通过hCa饮食抑制TRPV 6以实现其在结肠中的保护作用。
Dietary calcium is believed to reduce colon cancer risk, but the mechanism by which this occurs is poorly understood. Employing the Citrobacter rodentium-induced transmissible murine colonic hyperplasia (TMCH) model, we previously showed that a high-calcium diet (hCa) significantly abrogated hyperplasia in the distal colons of NIH-Swiss mice. Here, we explored the mechanism of dietary protection by hCa by analyzing the expression of genes involved in the regulation of Ca uptake/flux in the intestinal epithelium, including the Ca-sensing receptor, vitamin D receptor, Ca binding protein, and transient receptor potential cation channels, subfamily V, members 5 and 6 (TRPV5/6). Interestingly, while TRPV6 expression increased significantly during TMCH, the expression of the other gene products was unchanged. This elevated TRPV6 expression was significantly abrogated by a hCa diet. Immunofluorescence revealed apical membrane localization of TRPV6 in the normal colon, whereas during TMCH we observed intense apical pole and cytoplasmic staining along the entire longitudinal crypt axis, including the expanded proliferating zone. The hCa diet reversed this effect. In humans, overexpression of TRPV6 was associated with early-stage colon cancer, and in colon carcinoma cells, inhibition of TRPV6 expression by small interfering RNA inhibited their proliferation and induced apoptosis. TRPV6 small interfering RNA also diminished the transcriptional activity of the calcium-dependent nuclear factors in activated T cells. Thus the aberrant overexpression of TRPV6 contributes to colonic crypt hyperplasia in mice and to colon cancer cell proliferation in humans. Therefore, it is likely that suppression of TRPV6 by a hCa diet is required for its protective effects in the colon.